Experimental animals serve as useful models for studying human diseases. Advances in transgenic and targeted mutation technology have made the mouse not only a successful surrogate organism for human genome analysis, but also the most valuable model system to investigate the genetics and pathogenesis of human diseases. The valid interpretation of experimental results obtained from mouse studies depends upon the assurance that the mouse models used are genetically pure and well defined. For this reason, researchers have traditionally used inbred strains for experiments, because these mice, in contrast to outbred mouse stocks, offer uniformity and constancy of genotypes. Mice of inbred strains can be repeatedly accessed as homogeneous experimental individuals, with predictable phenotypes and defined allelic composition.
The constancy of genotype in inbred strain mice, however, is never fully realized because both new mutations arise and gradually accumulate together with continual allele fixation of residual heterozygosity. These changes in genotype within inbred mice is known as genetic drift. At each generation, there is a likelihood of spontaneous new mutations arising. These mutations first occur as heterozygous mutations. When both founders of an inbred strain, by chance, become homozygous for a spontaneous mutation, this mutation becomes fixed in the inbred strain, and all later generations of this inbred mouse strain will carry this mutation.
Genetic drift as a result of the rise of spontaneous mutations will impact genetic analysis performed on animals derived from an inbred strain. The valid interpretation of experimental data generated using inbred animals is undermined by genetic drift. A recent publication illustrates this point. In 2001, Specht and Schoepfer discovered a chromosomal deletion in C57BL/6JOlaHsd mice (See Specht and Schoepfer, Deletion of the alpha-synuclein locus in a subpopulation of C57BL/6J inbred mice, BMC Neurosci. 2, 11 (2001). The mutation was the ablation of the more than 79 kb of the alpha-synuclein locus. This gene encodes a presynaptic telencephalic protein that has been implicated in the etiology of Parkinson and Alzheimer diseases. Many researchers have used C57BL/6JOlaHsd mice as a wild-type control for their experiments or to backcross with other mutations, unaware of this problem. Now their experimental results need to be re-evaluated in light of the alpha-synuclein deletion present in the strain. See Wotjak, C57Black/Box? The importance of exact mouse strain nomenclature, Trends in Genetics 19: 183-184 (2003).
Moreover, researchers frequently need to compare data obtained from inbred animals over extended periods of time. Due to the effects of genetic drift, over time, inbred strain mice become genetically different from the “same” inbred mice at an earlier point in time. The longer the time span, the more likely a genetic differences will accumulate and become fixed. The existence of genetic drift thus undermines one's ability to carry out valid comparisons across extended periods of time.
For these reasons it is desirable to reduce genetic drift in inbred animal strains and maintain their genetic stability over protracted periods of time. There is a pressing need in the art for methods of maintaining genetic stability of inbred animal strains. Such methods are provided herein.